Recurrent respiratory papillomatosis (RRP) is a potentially life threatening disease caused by human papillomaviruses (HPVs). The disease is characterized by repeated growth of benign tumors, predominantly in the larynx but sometimes extending into the trachea and lungs. In the larynx, the papillomas impair the voice and cause airway obstruction. In the lungs, they are frequently fatal. There is no effective, safe medical treatment. Conventional treatment is surgical removal, but surgery does not prevent recurrence of disease, which is believed to be due to activation of latent HPV infection. Current experimental treatments only help a subset of patients, and those with pulmonary disease usually do not respond. The goal of this application is to test the hypothesis that treatment with celecoxib, an inhibitor of the inducible enzyme cyclooxygenase-2 (COX-2), will prevent or reduce recurrent disease when used as an adjunct to surgery. The application is based on our preliminary studies of elevated levels of COX-2 and the prostaglandins it produces in papillomas, in vitro results supporting a role for COX-2 in the pathophysiology of RRP, studies by other showing anti-tumor properties of celecoxib in other diseases, including HPV-induced disease, and preliminary clinical data treating patients with RRP. The study is a Phase II randomized double blind placebo controlled multi-center clinical trial to assess the efficacy of celecoxib therapy for RRP. Patients ages 18 or older with moderate to severe disease will be eligible for enrollment. After a 6 month evaluation period to define rate of papilloma growth, patients randomized to an early treatment arm with 12 months of celecoxib therapy followed by 12 months on placebo, or a delayed treatment arm receiving placebo for 12 months followed by 12 months on celecoxib. All patients will be in the study for 2.5 years. Aim 1, the primary aim of the study is to determine efficacy of celecoxib treatment and whether response is sustained when celecoxib is stopped. Aim 2 will correlate possible variation in response with select clinical and demographic characteristics. Aims 3-4 will address possible mechanism of action, determining whether molecular markers are consistent with celecoxib is acting through a COX-2 dependent or independent mechanism (Aim 3), and whether celecoxib therapy reduces persistence of latent HPV DMA (Aim 4). Together, these aims will determine whether celecoxib therapy is effective in treating respiratory papillomas, determine which patients will respond, and increase our understanding of the effects of celecoxib on this disease.